My Inspections are More Rigorous than Yours

December 22, 2016

In the past month, three of the seven posted reports of Eudra GMP non-complianceaddressed sites in the US, the others were located in India. Similarly, FDA imposed an import alert against a Teva Pharmaceuticals site in Hungary in the same time period and also issued warning letters to BBT Biotech in Germany and Corden Pharma in Italy. And on June 21, FDA issued an import alert for a site in the UK. Perhaps this is the beginning of a my-inspectors-are-more-rigorous-than-yours type of unofficial competition as these two agencies try to rely more on each other’s inspections and are testing the limits and validity of that assumption. Also interesting is that the European inspections evaluated investigational product manufacture, something FDA does only rarely or for-cause. Maybe the Europeans are making that point with these three inspections. Below we cover the two EU reports that published this week. The third report of non-compliance was issued to Bend Research Institute in Bend, OR on May 16, 2016.

This week the MHRA published two reports of GMP non-compliance issued to two Pharmaceutics International Inc. sites in Maryland based on inspections conducted at the end of February, 2016. They include the always serious combination of data integrity and risk of cross contamination. This combination rarely ends without enforcement action of some type. Each is addressed separately below but common deficiencies have been identified at both sites.

Hunt Valley Site: Specific commercial products identified as being manufactured at this site include Ammonaps tablets, Ammonaps oral powder, Lutigest vaginal tablets and investigational products that were not specifically identified. Two critical deficiencies were identified including 1) failure to minimize the risk of cross contamination between hazardous and non-hazardous products manufactured in the same facility on shared equipment. I assume by ‘hazardous’ the MHRA means high potency medicinal products rather than non-pharmaceutical products and 2) Failure of the Quality Unit to perform their responsibilities, particularly ‘gross failure of change management’ that permitted use of an ‘unqualified HPLC system’ and quality investigation that did not include QRM principles. Three major deficiencies were identified including: ‘1) organisational data governance failures, particularly relating to generation and checking of analytical data obtained from electronic systems, and inadequate investigation into previous data integrity failures. 2) deficiencies in sterilisation and depyrogenation processes, and 3) insufficient control of aseptic operations to provide the required level of sterility assurance.’

The UK GMP certificate was withdrawn. The MHR recommends recall of product where alternative medicines exist, no future batches of non-critical product may be supplied to the EU while the report of non-compliance remains in effect. Regarding investigational products produced at the site, ‘The proposal to continue supply individual batches of investigational medicinal product should be submitted as a substantial amendment, supported by a risk assessment and demonstrating a positive benefit risk ratio for trial subjects. This should be authorised by the National Competent Authority.’ This is similar to the conditions imposed on Bend Research Institute in Bend, OR after a recent inspection and report of non-compliance by the competent authorities of Sweden.

Cockysville, MD Site: The products deemed to be non-compliant with EU GMPS include investigational products, both sterile and non-sterile. MHRA includes the ‘clarifying remark’ as follows: ‘The scope of this statement of non-compliance is limited to medicinal products considered non-critical to public health. Where manufacture and/or testing is continued for critical products, this should be supported by a documented risk assessment containing sufficient information to support activity on a risk management basis. The statement of non-compliance also applies to all investigational medicinal products (IMPs) manufactured by Pii and the manufacture and supply of these products should cease. The only exemption to this is where a trial sponsor can demonstrate that the benefit risk ratio remains positive and supports the continuation of a particular trial. Pii is required to carry out a risk assessment, in conjunction with the sponsor of each trial for which they manufacture IMP, to discuss such continuation of supply on a batch by batch basis.’

The deficiencies identified are the same as those identified at the Hunt Valley, MD site.

Recall of product is recommended where alternatives exist for medically necessary products. Further no additional batches of product are to be imported into the EU while the statement of non-compliance remains in force.

Regarding continuation of clinical trials using materials: ‘The proposal to continue supply individual batches of investigational medicinal product should be submitted as a substantial amendment, supported by a risk assessment and demonstrating a positive benefit risk ratio for trial subjects. This should be authorised by the National Competent Authority.’

FDAzilla’sSTORE identifies several recent FDA inspections at both Maryland sites. The most recent for the Cockeysville, MD site occurred in April 4, 2016. I think that was likely in response to information provided by the MHRA because the previous inspection at the site was just under a year ago, in May, 2015. The most recent inspection at the Hunt Valley, MD site also occurred in May 2015. I would expect FDA to re-inspect them shortly. It’s unlikely that the MHRA identified deficiencies appeared only in the past year, so it might be that FDA did not identify them in the most recent inspection or did not deem them so critical as did MHRA.

Get a Free Sample of Warning Letter Deficiencies "Data Integrity", newly published BLOG items and updates on additions to our store.